The staff neurologist and medical director of the Barlo Multiple Sclerosis Program at St Michaels Hospital provided insight on the use of biomarkers to improve management of RIS and uncover more as it relates to MS.
Since its introduction for clinical use in the early 1980s, MRI has become increasingly available and played a pivotal role in understanding the differences between radiologically isolated syndrome (RIS) and multiple sclerosis (MS). Before the introduction of MRI, incidental findings suggestive of MS were only encountered on autopsies, and even after being formally defined for the first time in 2009 by Darin T. Okuda, MD, et al,1,2 clinicians still are without answers as to why some cases of RIS do and don’t develop into MS.
Okuda and his colleagues defined RIS as the presence of incidentally identified central nervous system white matter abnormalities that meet several specific MRI criteria. Despite the growing knowledge and research of RIS, the field remains without consensus guidelines on the management of the disease. Oftentimes, clinicians have carefully monitored these patients with a wait-and-see approach, which has not been favored as ideal by experts like Jiwoh Oh, MD, PhD.
Oh, a staff neurologist and medical director of the Barlo Multiple Sclerosis Program at St Michaels Hospital, University of Toronto, recently gave a talk at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022, February 24-26, in West Palm Beach, Florida, on the RIS/MS prodrome. In her presentation, she noted that RIS represents a valuable opportunity to evaluate the earliest stages of MS. In this newest iteration of NeuroVoices, NeurologyLive® caught up with Oh following the meeting to discuss her talk, the role of biomarkers in patients with RIS, and the need to create recommendations on the management of these patients.
Jiwoh Oh, MD, PhD: In a nutshell, I discussed an entity known as radiologically isolated syndrome, which is referring to people with what we think of as pre-symptomatic MS. These are people who happen to get an MRI for one reason or another, not related to any typical neurological symptoms of MS. But they get an MRI and there are lesions that look exactly like what we see in MS. It’s not that common, but every neurologist has a number of these patients in their practice. It’s challenging because we don’t have good evidence-based guidelines as to how to manage these people. We do know that a significant proportion have a risk of developing MS anywhere from 5 to 10 years, but then there’s also still a pocket of people that don’t develop MS. From a clinical standpoint, we need something that helps us predict who will develop MS and therefore needs to be on chronic treatment, versus people that we can reassure.
This is where potentially some advanced imaging measures have a role. I tried to summarize the existing literature on some of the advanced imaging measures, and then focused on a number of advanced measures that our group has been working on and that there’s a lot of interest in the field in general. Some of the measures I looked at in more detail include some advanced quantitative measures in the spinal cord, as well as imaging measures such as central vein signand paramagnetic rim lesions. We found some interesting findings in our patients. Over time, we can prospectively show that some, or a combination of these measures, have predictive value. It might be very helpful from a clinical standpoint.
Some of the quantitative spinal cord MRI measures that our group has looked at in RIS, while useful scientifically, are difficult to acquire from a technical standpoint. Ultimately, what determines whether an MRI measure is useful is not just how strongly correlated it is with the clinical measure of interest, but it’s how easily you can acquire it. It’s just a bit too difficult, but of the measures we talked about, I think based on what we know about them, paramagnetic rim lesions have a lot of potential. Obviously, longitudinal data will determine its utility.
But what we’ve found is that in patients with RIS, the vast majority, over 60%, have at least one PRL [paramagnetic rim lesion]. When we followed this cohort longitudinally, we might be able to say, “if you have a certain number of PRLs, your likelihood of developing MS is very high, therefore you should be on treatment.” That’s what I hypothesize, but that needs to be validated. Of the measures that we discussed, PRLs have the highest potential.
There’s no clear consensus as to how to manage these patients. In my presentation, I talked about what the general approach is. You can either follow these patients closely, annually, clinically, and using MRI. You can treat them if you think they’re at high risk, or sometimes people will tell patients to come back if they have any issues. I’m not brave enough to do that. A lot of patients would feel uncomfortable not having regular follow-up. The bottom line is, we don’t know whether we need to treat most of these people with MS medications or not. The reason for that is that we don’t have phase 3 trial evidence.
What do we need? First of all, some of the phase 3 trials are wrapping up. Hopefully in the next year or two, we’ll have some guidance. But I think still having RIS with this phase 3 data may not be enough, because there still are a proportion of people that won’t develop symptoms. Again, that’s why these imaging or fluid biomarkers will be useful. Hopefully, based on the phase 3 clinical trial data, we’re able to say, “Yes, there’s a proportion of patients that benefit from being on treatment,” but knowing who to treat. It’s a tough sell telling someone who feels fine that they need to be on a regular medication that potentially has side effects. What we need is phase 3 clinical trial data with better biomarkers so that we’re able to say, “Yes, you need to be on treatment. Yes, these treatments have side effects, but it would be very helpful for you because you’re at very high risk of developing MS.”
Yes, I think so. But the term has been around for a long time. In fact, the term RIS was coined in 2009. Even before neurologists had access to these MRIs, these people with lesions without clinical symptoms have been around. Fortunately, we’re recognizing in the field that with established MS, it’s really important to treat as early as possible. There’s a general focus in the field on earlier stages of MS, which then takes you to RIS. Maybe 10 years ago there wasn’t as much recognition of the importance of RIS, but I think currently, and especially shown at ACTRIMS, there was a focus on the prodrome of MS and RIS. I think we’re recognizing as a field how important it is to study these people because they represent the earliest detectable stage of MS.
Transcript edited for clarity. Click here for more iterations of NeuroVoices.